A Harvard Medical School-led study, published in Cell uncovers how a tiny molecular change in gut bacteria helps maintain immune balance. The research in mice shows that a small structural tweak in lipid A a fatty-sugar molecule on the bacterial surface determines whether colon immune cells trigger inflammation or remain calm. While disease-causing bacteria typically carry a six-chain form of lipid A that provokes strong immune responses many gut-friendly bacteria feature a rare four-chain version that instead promotes immune-calming signals and supports protective regulatory T cells. These findings supported by the NIH and Department of Defense open new possibilities for microbiome-targeted therapies to prevent or treat inflammatory bowel diseases such as Crohn’s.

Our research shows that even small variations in microbial molecules can have a major impact on immune responses said senior author Dennis Kasper the HMS William Ellery Channing Professor of Medicine at Brigham and Women’s Hospital and professor of immunology at the Blavatnik Institute at HMS. It’s not just the presence of gut bacteria but the specific structure of their molecules that shapes how the immune system reacts.

The study revealed that the uncommon four-chain version of lipid A prompts immune cells to release inflammation-reducing interferon beta. When this molecule interacts with the immune cell surface receptor TLR4 typically responsible for rallying immune defenses it instead triggers interferon beta production. This signaling helps sustain regulatory T cells (Tregs) which act as brakes on the immune system preventing it from mistakenly attacking harmless targets like food proteins or beneficial gut microbes.

In experiments with mice modeling human inflammatory bowel disease those fed the four-chain version of lipid A showed significantly reduced colon inflammation compared to untreated mice, whose colons developed severe colitis. The treated mice exhibited minimal signs of inflammation and maintained healthier colons. These findings suggest new strategies for modulating colon immunity using lab-designed bacterial molecules to target gut inflammation said Kasper.

Source: https://hms.harvard.edu/news/how-subtle-bacterial-shifts-keep-gut-inflammation-bay